CN113164436A

CN113164436A - Pharmaceutical composition

Info

Publication number: CN113164436A
Application number: CN201980077536.4A
Authority: CN
Inventors: 岩田见二; 藏本诚; 小阪和德
Original assignee: Kyowa Hakko Kirin Co Ltd
Current assignee: Kyowa Kirin Co Ltd
Priority date: 2018-11-27
Filing date: 2019-11-27
Publication date: 2021-07-23
Also published as: TW202038918A; JPWO2020111089A1; WO2020111089A1; KR20210096162A

Abstract

The present invention provides a pharmaceutical composition having improved stability of bardoxolone methyl or a pharmaceutically acceptable salt thereof. A pharmaceutical composition containing bardoxolone methyl or a pharmaceutically acceptable salt thereof, a disintegrant, and a binder, which has a coating film, is used.

Description

Pharmaceutical composition

Reference to related applications

The present patent application claims priority based on japanese application No. 2018-221650, filed on 27.11.2018, the entire disclosure of which is incorporated by reference as part of the disclosure of the present invention.

Technical Field

The present invention relates to a pharmaceutical composition, and more particularly, to a pharmaceutical composition containing bardoxolone methyl or a pharmaceutically acceptable salt thereof.

Background

As a synthetic terpenoid compound, bardoxolone Methyl (2-cyano-3, 12-dioxooleana-1, 9(11) -diene-28-oate) (Methyl 2-cyanoo-3, 12-dioxoleana-1, 9(11) -dien-28-oate) (hereinafter, sometimes referred to as "compound a") represented by the following formula is known (see patent document 1), and it is also known that this bardoxolone Methyl has a polymorphic form (see patent document 2).

[ chemical formula 1]

It has been clarified that bardoxolone methyl is a low molecular weight compound that activates transcription factor Nrf2 (which plays a central role in stress defense reactions in vivo), has a wide range of antioxidant stress and anti-inflammatory effects, and has a potent anti-inflammatory effect and anti-tumor effect in preclinical studies and human clinical trials. Bardoxolone methyl is also known to exhibit significant anticancer activity particularly in advanced cancer patients, and in addition, to have the ability to improve renal function, insulin resistance, measurement of blood glucose control, and systemic circulatory diseases in patients with chronic kidney disease caused by type 2 diabetes (see patent document 3). In addition, clinical trials have shown that the eGFR value (an index of renal function) is significantly improved by the administration of bardoxolone methyl (see non-patent document 1, non-patent document 2, and non-patent document 3).

Although studies have been conducted for designing a pharmaceutical composition suitable for bardoxolone methyl (see patent document 4), further stabilization of bardoxolone methyl is still sought.

Documents of the prior art

Patent document

Patent document 1: WO1999/65478 publication

Patent document 2: WO2009/023232 publication

Patent document 3: WO2009/089545 publication

Patent document 4: WO2010/093944 publication

Non-patent document

Non-patent document 1: n Engl J Med, 2013, 369, p2492-2503

Non-patent document 2: AM J Nephrol, 2011, 33, p469-476

Non-patent document 3: n Engl J Med, 2011, p327-336

Disclosure of Invention

Problems to be solved by the invention

The present invention provides a stable pharmaceutical composition which contains bardoxolone methyl or a pharmacologically acceptable salt thereof and is acceptable as a pharmaceutical.

Means for solving the problems

The present invention relates to the following (1) to (26).

(1) A pharmaceutical composition comprising bardoxolone methyl or a pharmaceutically acceptable salt thereof, a disintegrant and a binder, said pharmaceutical composition having a coating film.

(2) The pharmaceutical composition according to (1), wherein the disintegrant is at least 1 selected from the group consisting of crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, partially gelatinized starch, and starch.

(3) The pharmaceutical composition according to (2), wherein the disintegrant is at least 1 selected from the group consisting of crospovidone, croscarmellose sodium, and low substituted hydroxypropyl cellulose.

(4) The pharmaceutical composition according to any one of (1) to (3), wherein the disintegrant is contained in an amount of 0.1 to 20 parts by weight per 100 parts by weight of the pharmaceutical composition.

(5) The pharmaceutical composition according to any one of (1) to (4), wherein the binder is at least 1 selected from the group consisting of hydroxypropyl cellulose, methyl cellulose, hypromellose, carboxymethyl cellulose, carboxymethylethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxypropyl starch, carboxyvinyl polymer, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, methacrylic acid copolymer, polyethylene glycol, starch, gelatin, dextrin, pullulan, agar, and gum arabic.

(6) The pharmaceutical composition of (5), wherein the binder is at least 1 selected from the group consisting of hydroxypropyl cellulose, hypromellose, polyvinyl alcohol, and polyvinylpyrrolidone.

(7) The pharmaceutical composition according to any one of (1) to (6), wherein the binder is contained in an amount of 0.1 to 30 parts by weight based on 100 parts by weight of the pharmaceutical composition.

(8) The pharmaceutical composition according to any one of (1) to (7), which further comprises a stabilizer.

(9) The pharmaceutical composition of (8), wherein the stabilizer is an organic acid.

(10) The pharmaceutical composition of (9), wherein the organic acid is fumaric acid and/or malic acid.

(11) The pharmaceutical composition according to any one of (1) to (10), wherein the coating film comprises 1 or more coating agents selected from the group consisting of water-soluble polymers, lactose, white sugar, mannitol, titanium oxide, talc, calcium carbonate, and triacetin.

(12) The pharmaceutical composition of (11), wherein the water-soluble polymer is at least 1 selected from the group consisting of polyethylene glycol, polyvinyl alcohol polyethylene glycol graft copolymer, polyvinylpyrrolidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, and polyvinyl alcohol methyl acrylate copolymer.

(13) The pharmaceutical composition according to (11) or (12), wherein the coating film further contains a coloring agent.

(14) The pharmaceutical composition according to (13), wherein the coloring agent comprises 1 or more selected from the group consisting of yellow iron sesquioxide, iron oxide, and titanium oxide.

(15) The pharmaceutical composition according to any one of (1) to (14), which comprises 0.1 to 100 parts by weight of the coating agent per 100 parts by weight of the coating film.

(16) The pharmaceutical composition according to any one of (1) to (15), which further comprises a glossing agent.

(17) The pharmaceutical composition of (16), wherein the gloss agent is carnauba wax and/or magnesium stearate.

(18) The pharmaceutical composition according to any one of (1) to (17), wherein,

comprises 0.1 to 20 parts by weight of bardoxolone methyl or a pharmaceutically acceptable salt thereof relative to 100 parts by weight of the pharmaceutical composition,

the adhesive comprises 3-20 parts by weight of adhesive based on 100 parts by weight of the pharmaceutical composition,

0.1 to 15 parts by weight of a disintegrant per 100 parts by weight of the pharmaceutical composition,

the coating agent is contained in an amount of 50 to 90 parts by weight based on 100 parts by weight of the coating film.

(19) The pharmaceutical composition according to any one of (1) to (18), wherein bardoxolone methyl is amorphous.

(20) The pharmaceutical composition according to any one of (1) to (19), which is a solid preparation.

(21) The pharmaceutical composition according to (20), wherein the solid preparation is a tablet.

(22) A blister pack comprising the pharmaceutical composition according to any one of (1) to (21), and a film and an aluminum foil laminated with a polymer.

(23) The blister pack according to (22), wherein the film obtained by laminating polymers is a film obtained by laminating 1 or more polymers selected from the group consisting of polypropylene, polyvinyl chloride, polyvinylidene chloride and polychlorotrifluoroethylene.

(24) A pharmaceutical pack comprising a package in which the blister pack of (22) or (23) is sealed.

(25) The pharmaceutical package according to (24), wherein the package is an aluminum bag.

(26) The pharmaceutical package according to (24) or (25), wherein a deoxidant and/or a desiccant are further enclosed in the package.

According to the present invention, a pharmaceutical composition containing bardoxolone methyl or a pharmacologically acceptable salt thereof, a disintegrant, and a binder and having a coating film can be prepared, thereby improving the stability of bardoxolone methyl or a pharmacologically acceptable salt thereof.

Drawings

FIG. 1 is a graph showing a comparison of the dissolution rates (%) of the plain film 4 with time before (at the beginning of) storage, after 1 month (1 month), after 2 months (2 months), and after 3 months (3 months). The vertical axis represents dissolution rate (%), and the horizontal axis represents time (minutes).

FIG. 2 is a graph showing a comparison of the dissolution rates (%) of the plain film 5 with time before (at the beginning of) storage, after 1 month (1 month), after 2 months (2 months), and after 3 months (3 months). The vertical axis represents dissolution rate (%), and the horizontal axis represents time (minutes).

FIG. 3 is a graph showing a comparison of the dissolution rates (%) of the plain film 6 with time before (at the beginning of) storage, after 1 month (1 month), after 2 months (2 months), and after 3 months (3 months). The vertical axis represents dissolution rate (%), and the horizontal axis represents time (minutes).

FIG. 4 is a graph showing a comparison of the dissolution rates (%) of the plain film 7 with time before (at the beginning of) storage, after 1 month (1 month), after 2 months (2 months), and after 3 months (3 months). The vertical axis represents dissolution rate (%), and the horizontal axis represents time (minutes).

Detailed Description

The pharmaceutical composition of the present invention is a pharmaceutical composition containing bardoxolone methyl (hereinafter, also referred to as "compound a") or a pharmaceutically acceptable salt thereof, a binder, and a disintegrant, and having a coating film. The chemical structure of compound a can be produced by the method disclosed in international publication No. 1999/65478 (patent document 1) or a method conforming thereto, as described above.

In the present invention, the term "pharmaceutically acceptable" means useful for the preparation of a pharmaceutical composition which is generally safe, nontoxic and free from biological and other problems, and is accepted not only for human pharmaceutical use but also for veterinary use.

In the present invention, the "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt as defined above and having a desired pharmacological activity. Examples of such salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as maleic acid, methanesulfonic acid, and oxalic acid. As pharmaceutically acceptable salts there may also be mentioned the base addition salts which are formed when an acidic proton present is capable of reacting with an inorganic or organic base. Examples of the pharmaceutically acceptable inorganic base include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Examples of the pharmaceutically acceptable organic base include ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-methylglucamine.

Examples of the pharmaceutically acceptable salt of compound a include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and organic base salts such as amine salt. The compound a of the present invention or a pharmaceutically acceptable salt thereof includes any of intramolecular salts, adducts, solvates, or hydrates thereof, and the like.

In the compound a or a pharmaceutically acceptable salt thereof, there are also cases where stereoisomers such as geometric isomers and optical isomers, tautomers, and the like may exist, and the present invention includes all possible isomers including those described above and mixtures thereof.

Some or all of the atoms in compound a or a pharmaceutically acceptable salt thereof may be substituted with the respective corresponding isotopic atoms, and derivatives thereof substituted with these isotopic atoms are also included in the present invention.

The compound a or a pharmaceutically acceptable salt thereof of the present invention also includes an active metabolite of the compound a (as an active metabolite, for example, various conjugates and the like are exemplified) or a pharmaceutically acceptable salt thereof.

The content of compound a or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention is not particularly limited, but is preferably 0.1 to 20 parts by weight, more preferably 1 to 20 parts by weight, even more preferably 2 to 15 parts by weight, and particularly preferably 2 to 10 parts by weight, based on 100 parts by weight of the pharmaceutical composition.

Compound a may be crystalline (form a), amorphous (form B) or a mixture thereof, and according to a preferred embodiment of the present invention, compound a is mainly amorphous (form B), and preferably contains 50 to 100 parts by weight of amorphous (form B), more preferably 80 to 99.9 parts by weight, and still more preferably 95 to 99 parts by weight, based on 100 parts by weight of compound a. According to a more preferred embodiment of the present invention, the compound a is an amorphous solid dispersion in a glassy matrix, and is, for example, a product obtained by spray-drying a solution or suspension of a mixture of the compound a and a methacrylic acid copolymer. Such a solid dispersion is preferably obtained by mixing compound a and a methacrylic acid copolymer in a ratio of 4: 6, and more preferably a product obtained by spray-drying the mixture of the compound A and the methacrylic acid copolymer.

In order to obtain a solid dispersion of the amorphous compound a, it can be produced by using various separation techniques. Examples of suitable methods for producing the solid dispersion of the amorphous compound a include conventional various thermal methods (e.g., hot melt extrusion method), solvent method, and thermal/solvent method (e.g., spray drying or fluidized immersion method of granules).

As for the method for producing a solid dispersion, according to "the first line of techniques for oral preparation of poorly water-soluble drugs" (CMC published, 2016) (reference 1), from the viewpoint of stability of an amorphous drug in a solid dispersion, the higher the glass transition point of the solid dispersion, the better. It is also described that, from the viewpoint of production, the exhaust gas temperature at the time of spray drying is preferably not higher than the glass transition point of the solid dispersion (see page 195 of reference 1). Examples of typical solvents that can be used in the solid dispersion by the spray drying method include water, methanol, ethanol, acetone, and methylene chloride, and suitable solvents are selected from these solvents according to the drug and the carrier. It is described that: since the production efficiency can be improved when the drug and the carrier are dissolved at high concentrations, the drug concentration of the spray solution is preferably 50mg/mL or more (see reference 1, page 196).

The pharmaceutical compositions of the present invention typically comprise a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof. The "therapeutically effective amount" as used herein means an amount which can provide a desired pharmacological effect when the pharmaceutical composition of the present invention is administered to a patient. In general, a therapeutically effective amount may be determined empirically with reference to clinical parameters of the patient.

The disintegrant contained in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a drug, and examples thereof include PVP-based disintegrants such as crospovidone; cellulose-based disintegrants such as croscarmellose sodium, low-substitution hydroxypropylcellulose, carboxymethylcellulose, and carboxymethylcellulose calcium; the starch-based disintegrant such as sodium carboxymethyl starch, partially gelatinized starch, or starch is preferably 1 or more selected from the group consisting of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethylcellulose calcium, sodium carboxymethyl starch, partially gelatinized starch, and starch, more preferably 1 or more selected from the group consisting of PVP-based disintegrants and cellulose-based disintegrants, still more preferably 1 or more selected from the group consisting of crospovidone, croscarmellose sodium, and low-substituted hydroxypropyl cellulose, still more preferably croscarmellose sodium or low-substituted hydroxypropyl cellulose, and particularly preferably low-substituted hydroxypropyl cellulose. Here, the low-substituted hydroxypropylcellulose is low-substituted hydroxypropylether of cellulose, and when the low-substituted hydroxypropylcellulose is dried and then quantified, it contains 5.0 to 16.0% of hydroxypropoxy (-OC)₃H₆OH：75.09)。

The content of the disintegrant in the pharmaceutical composition of the present invention is not particularly limited as long as it is an amount usable as a drug, and is preferably 0.1 to 20 parts by weight, more preferably 0.1 to 18 parts by weight, and further preferably 0.1 to 15 parts by weight, based on 100 parts by weight of the pharmaceutical composition.

The binder contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is a substance that can be used as a drug, but is preferably at least 1 selected from the group consisting of hydroxypropyl cellulose, hypromellose (hydroxypropylmethyl cellulose), methyl cellulose, carboxymethyl cellulose, carboxymethylethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxypropyl starch, carboxyvinyl polymer, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, methacrylic acid copolymer, polyethylene glycol, starch (more preferably corn starch, potato starch), gelatin, dextrin, pullulan, agar, and gum arabic, and more preferably selected from the group consisting of hydroxypropyl cellulose, hypromellose, hydroxypropyl methylcellulose, and gum arabic, More preferably, the polyvinyl alcohol is one selected from the group consisting of polyvinyl alcohol and polyvinylpyrrolidone, and more preferably hydroxypropyl cellulose or hypromellose, and particularly preferably hypromellose.

The content of the binder in the pharmaceutical composition of the present invention is not particularly limited as long as it is an amount usable as a drug, and is preferably 0.1 to 30 parts by weight, more preferably 0.5 to 25 parts by weight, and further preferably 3 to 20 parts by weight, based on 100 parts by weight of the pharmaceutical composition.

The pharmaceutical composition of the present invention may contain, in addition to the compound a, a disintegrant, and a binder, other additives that can be used as a drug, for example, 1 or more additives selected from the group consisting of a stabilizer, an excipient, a lubricant, a colorant, a flow agent, and a gloss agent, which are used in pharmaceutical preparations. The stabilizer, the excipient, the lubricant, the colorant, the flow agent, and the gloss agent in the present specification are not limited to the respective applications (functions) described above, and may be used for other applications (functions) (for example, a binder is used as the excipient, and the excipient is used as the binder).

The stabilizer contained in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a drug, and examples thereof include organic acids and calcium carbonate, and organic acids are preferable. Examples of the organic acid contained in the pharmaceutical composition of the present invention include fumaric acid, malic acid, citric acid hydrate, citric anhydride, succinic acid, adipic acid, tartaric acid, maleic acid, and the like, and fumaric acid and/or malic acid is preferable, and fumaric acid is more preferable. By adding fumaric acid and/or malic acid to the pharmaceutical composition of the present invention, a good preparation having a small total amount of similar substances and higher stability can be prepared.

The content of the stabilizer (preferably, an organic acid) in the pharmaceutical composition of the present invention is not particularly limited as long as it is an amount usable as a drug, and is preferably 0.01 to 30 parts by weight, more preferably 0.05 to 10 parts by weight, and further preferably 0.1 to 5 parts by weight, based on 100 parts by weight of the pharmaceutical composition.

The excipient contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is a substance that can be used as a drug, and examples thereof include sugar, sugar alcohol, crystalline cellulose, silicic acid-treated crystalline cellulose (silicic acid-treated crystalline cellulose), inorganic salts, and the like, and preferably lactose, white sugar, maltose, sucrose, mannitol, sorbitol, erythritol, maltitol, xylitol, glucose, crystalline cellulose, silicic acid-treated crystalline cellulose, calcium monohydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, and calcium phosphate, and 2 or more of these excipients may be used in combination, more preferably lactose (preferably, lactose hydrate), mannitol, silicic acid-treated crystalline cellulose, and 2 or more of these excipients may be used in combination.

The content of the excipient in the pharmaceutical composition of the present invention is not particularly limited as long as it is an amount usable as a drug, and the excipient is preferably contained in an amount of 0.1 to 99.9 parts by weight, more preferably 1 to 95 parts by weight, and further preferably 10 to 90 parts by weight, based on 100 parts by weight of the pharmaceutical composition.

The lubricant contained in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a drug, and for example, magnesium stearate, calcium stearate, sodium lauryl sulfate, talc, glyceryl monostearate, light silicic anhydride, sodium stearyl fumarate, and sucrose fatty acid esters (for example, sucrose stearate, sucrose palmitate, sucrose oleate, and sucrose laurate) are preferable, and 2 or more of these lubricants can be used in combination.

The content of the lubricant in the pharmaceutical composition of the present invention is not particularly limited as long as it is an amount usable as a drug, and is preferably 0.05 to 10 parts by weight, more preferably 0.1 to 5 parts by weight, and further preferably 0.5 to 3 parts by weight, based on 100 parts by weight of the pharmaceutical composition.

The colorant contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is a substance that can be used as a drug, and preferably contains 1 or more selected from the group consisting of yellow iron trioxide, titanium oxide, talc, iron trioxide, black iron oxide, copper chlorophyll, sodium copper chlorophyllin, carbon black, medicinal charcoal, food color, licorice extract, green tea dust, riboflavin butyrate, riboflavin sodium phosphate, and octyldodecyl myristate, and more preferably contains 1 or more selected from the group consisting of yellow iron trioxide, iron oxide, and titanium oxide.

The content of the colorant in the pharmaceutical composition of the present invention is not particularly limited as long as it is an amount usable as a drug, and may be, for example, 0.01 to 5 parts by weight based on 100 parts by weight of the pharmaceutical composition.

The flow agent contained in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a drug, and examples thereof include hydrated silicon dioxide, light silicic anhydride, synthetic aluminum silicate, synthetic hydrotalcite, dried aluminum hydroxide gel, kaolin, calcium silicate, magnesium aluminosilicate, talc, and the like, and 2 or more kinds of these flow agents can be used in combination.

The content of the flowable agent in the pharmaceutical composition of the present invention is not particularly limited as long as it is an amount usable as a drug, and may be, for example, 0.01 to 5 parts by weight based on 100 parts by weight of the pharmaceutical composition.

The glossing agent contained in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a drug, and examples thereof include carnauba wax, shellac, beeswax, hardened oil, and magnesium stearate, and 2 or more of these glossing agents may be used in combination, and carnauba wax and/or magnesium stearate are preferable.

The content of the gloss agent contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is an amount usable as a drug, and is preferably 0.0001 to 100 parts by weight, more preferably 0.001 to 10 parts by weight, and further preferably 0.01 to 1 part by weight, based on 100 parts by weight of the pharmaceutical composition.

The pharmaceutical composition of the present invention has a coating film. The coating film can be provided, for example, by coating a base preparation (for example, base tablet) containing compound a or a pharmaceutically acceptable salt thereof, a disintegrant, and a binder. The coating treatment may be performed, for example, by: the coating solution containing the coating agent is sprayed to a base preparation (e.g., base tablet) containing compound a by a spray coating method or the like. The coating agent is used by dissolving, suspending, dispersing or the like in a coating liquid, and examples of the solvent constituting the coating liquid include water, alcohols such as methanol and ethanol, and water is more preferable.

The coating film of the pharmaceutical composition of the present invention is not particularly limited, and preferably contains 1 or more coating agents selected from the group consisting of water-soluble polymers, lactose, white sugar, mannitol, titanium oxide, talc, calcium carbonate, and triacetin, and more preferably triacetin.

The water-soluble polymer is not particularly limited as long as it can be used as a drug, and is preferably 1 or more selected from the group consisting of polyethylene glycol, a polyvinyl alcohol polyethylene glycol graft copolymer, polyvinylpyrrolidone, hypromellose, hydroxypropylcellulose, polyvinyl alcohol, and a polyvinyl alcohol methyl acrylate copolymer.

The coating film of the pharmaceutical composition of the present invention preferably further contains a coloring agent, and the coloring agent more preferably contains 1 or more selected from the group consisting of yellow iron sesquioxide, iron oxide, and titanium oxide.

The coating agent in the coating film is not particularly limited, and is preferably contained in an amount of 0.1 to 100 parts by weight, more preferably 1 to 95 parts by weight, and still more preferably 50 to 90 parts by weight, based on 100 parts by weight of the coating film.

The amount of the coating solution used in the coating treatment is not particularly limited as long as it can impart photostability or the like to the pharmaceutical composition, and the coating film (coating) is preferably 0.01 to 50 parts by weight, more preferably 0.05 to 30 parts by weight, and still more preferably 0.1 to 20 parts by weight in a dry state, relative to 100 parts by weight of the base preparation.

The pharmaceutical composition of the present invention preferably further contains a glossing agent, more preferably carnauba wax and/or magnesium stearate as a glossing agent.

The pharmaceutical composition of the present invention is preferably an oral preparation, and a flavoring agent and the like may be further added.

The shape of the pharmaceutical composition of the present invention is not particularly limited, but a solid preparation is preferable, a tablet, a powder, a fine granule, a capsule, or a dry syrup is more preferable, and a tablet is further preferable. By shaping the pharmaceutical composition of the present invention into a tablet, the following advantages are obtained: is easy to take, has sufficient physical strength, and is less prone to collapse compared with capsule.

The process for producing a tablet of the pharmaceutical composition of the present invention comprises granulating and tableting a mixture containing bardoxolone methyl or a pharmaceutically acceptable salt thereof as an active ingredient, a disintegrant, and a binder, and then subjecting the granulated mixture to a film coating step.

The method for producing the pharmaceutical composition of the present invention is not particularly limited, and for example, the pharmaceutical composition can be produced by a method generally used in the field of pharmaceutical technology such as compression molding, and can be produced by, for example, a direct compression method, a dry granulation method (a roll compression molding method, a slag tableting method, or the like), or the like. In any case, the following methods are preferred: for example, compound a or a pharmaceutically acceptable salt thereof, and additives such as a disintegrant and a binder are mixed, and granulated as necessary. Next, for example, in the case of preparing a tablet, a tablet is formed from the obtained dry granulated substance using a compression tableting machine. The tablet pressure may be, for example, from 300 to 3000kg/cm²Is appropriately selected from the range of (1). The tablet size is not particularly limited, but it is preferably 20 to 3000mg per 1 tablet by weight and 5 to 15mm in diameter. To pairWhen the coating treatment is performed on the plain tablets, the obtained plain tablets may be coated with a solution/dispersion in which the coating agent is dissolved/dispersed to form a coating. Examples of the solvent for dissolving/dispersing the coating agent include water, ethanol, isopropanol, and a mixed solvent thereof, and among these, water is preferred. The coating is performed using, for example, a conventional pan coater, a vented coater, a fluidized bed coater, a rotary fluidized coater, or the like.

Preferred embodiments of the pharmaceutical composition of the present invention include the following pharmaceutical compositions (preferably tablets):

the pharmaceutical composition comprises 0.1-20 parts by weight of compound A or pharmaceutically acceptable salt thereof relative to 100 parts by weight of the pharmaceutical composition,

the adhesive (preferably hypromellose) is contained in 0.1-30 weight parts relative to 100 weight parts of the pharmaceutical composition,

0.1 to 20 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose) per 100 parts by weight of the pharmaceutical composition,

the coating film contains 0.1 to 100 parts by weight of a coating agent (preferably, the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin) per 100 parts by weight of the coating film.

Another preferred embodiment of the pharmaceutical composition of the present invention is a pharmaceutical composition (preferably a tablet) as follows:

comprising 0.0001-10 parts by weight of a gloss agent (preferably carnauba wax and/or magnesium stearate) per 100 parts by weight of the pharmaceutical composition,

the stabilizer (preferably organic acid, more preferably fumaric acid) is contained in 0.01-30 parts by weight relative to 100 parts by weight of the pharmaceutical composition,

comprising 0.001 to 10 parts by weight of a gloss agent (preferably, carnauba wax and/or magnesium stearate) per 100 parts by weight of the pharmaceutical composition,

More preferred embodiments of the pharmaceutical composition of the present invention include the following pharmaceutical compositions (preferably tablets):

the adhesive (preferably hypromellose) is contained in 0.5-25 weight parts relative to 100 weight parts of the pharmaceutical composition,

0.1 to 18 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose) per 100 parts by weight of the pharmaceutical composition,

the coating film contains 1 to 95 parts by weight of a coating agent (preferably, the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin) per 100 parts by weight of the coating film.

Another more preferred embodiment of the pharmaceutical composition of the present invention is a pharmaceutical composition (preferably a tablet) comprising:

comprising 0.001 to 10 parts by weight of a gloss agent (preferably carnauba wax and/or magnesium stearate) per 100 parts by weight of the pharmaceutical composition,

the stabilizer (preferably organic acid, more preferably fumaric acid) is contained in 0.05-10 parts by weight relative to 100 parts by weight of the pharmaceutical composition,

As another preferred embodiment of the pharmaceutical composition of the present invention, the following pharmaceutical composition (preferably, tablet) is used:

the adhesive (preferably hypromellose) is contained in 3-20 parts by weight relative to 100 parts by weight of the pharmaceutical composition,

0.1 to 15 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose) per 100 parts by weight of the pharmaceutical composition,

the coating film contains 50 to 90 parts by weight of a coating agent (preferably, the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin) per 100 parts by weight of the coating film.

comprising 0.01 to 1 part by weight of a gloss agent (preferably carnauba wax and/or magnesium stearate) per 100 parts by weight of the pharmaceutical composition,

the stabilizer (preferably organic acid, more preferably fumaric acid) is contained in 0.1-5 parts by weight relative to 100 parts by weight of the pharmaceutical composition,

According to another aspect of the present invention, there is provided a method for improving the stability of bardoxolone methyl or a pharmaceutically acceptable salt thereof, comprising adding a disintegrant and a binder to bardoxolone methyl or a pharmaceutically acceptable salt thereof, and coating the mixture with a film. In addition, according to another preferred embodiment of the present invention, there is provided a method for reducing the total amount of a substance analogous to bardoxolone methyl or a pharmaceutically acceptable salt thereof, characterized by adding a disintegrant and a binder to bardoxolone methyl or a pharmaceutically acceptable salt thereof and subjecting the mixture to a coating film treatment. In such a method, as in the pharmaceutical composition of the present invention described above, other additives that can be used as a drug other than the compound a, the disintegrant, and the binder may be added, and for example, 1 or more additives selected from the group consisting of stabilizers, excipients, lubricants, colorants, flow agents, and glossers that are used in pharmaceutical preparations may be added.

The pharmaceutical composition of the present invention can be provided in an airtight container such as a bottle pack, a blister pack, or an aluminum bag. The material of the airtight container is not particularly limited as long as it can suppress the intrusion of moisture from the outside, and materials used for the purpose of moisture-proofing of contents which do not tolerate moisture in the field of pharmaceuticals and the like can be used.

The blister pack of the present invention comprises the above-mentioned pharmaceutical composition containing compound a and the like, and a film and an aluminum foil laminated with a polymer. The film obtained by laminating the polymers is not particularly limited as long as it is a film that can be generally used in a blister package, and is preferably a film obtained by laminating polymers such as polypropylene, polyvinyl chloride, polyvinylidene chloride, polychlorotrifluoroethylene (Aclar (trademark)), and the like, and more preferably polypropylene or hard vinyl chloride. The aluminum foil is not particularly limited as long as it is an aluminum foil usable for blister packs, and may be an aluminum foil that is generally used, and preferably an aluminum foil in which the amount of melamine resin in the adhesive is reduced. The method for producing the blister pack of the present invention is not particularly limited, and can be obtained by molding cells (pockets) in the film obtained by laminating the polymers, using a commonly used blister packaging machine, adding tablets, and sealing the aluminum foil by heat or the like.

The pharmaceutical package of the present invention is obtained by enclosing the above-described blister package in a package. The packaging body is not particularly limited as long as it is a packaging body that can be generally used in pharmaceutical packages, and is preferably an aluminum bag or the like. In this pharmaceutical package, a substance normally sealed in the pharmaceutical package may be sealed at the same time, and it is preferable to seal a deoxidizer and/or a desiccant at the same time as the blister package. The pharmaceutical package of the present invention may be manufactured by: the blister package and the like manufactured as described above are sealed in a package such as an aluminum bag and sealed with a heat sealer or the like.

Examples

The present invention will be described more specifically below with reference to examples, but the technical scope of the present invention is not limited to these examples.

Production example of film-coated tablet

Formulation example 1:

480.8g of a solid dispersion (produced by spray drying, hereinafter referred to as "solid dispersion" similarly) containing 40% by weight of Compound A (Methylpyridone), 1976.9g of silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma), 1715.4g of lactose hydrate (Japanese pharmacopoeia), 250.0g of hypromellose (TC-5E, manufactured by shin-Etsu chemical Co., Ltd.), 500.0g of low-substitution hydroxypropylcellulose (L-HPC, manufactured by shin-Etsu chemical Co., Ltd.), and 38.5g of light silicic anhydride (Adsolider101, manufactured by Freund Corporation) were mixed by using a mixer (TBM-25). To the mixture was added 19.2g of magnesium stearate, and further mixed. The mixture was dry granulated and granulated using a roll press (CCS-220, manufactured by Powrex Co., Ltd.). Magnesium stearate in an amount of 0.38 wt% with respect to the obtained whole granules was added and mixed to obtain a mixed product for tableting. Tablets (weight: 130mg, shape of tablet: round (diameter: 7mm)) were produced using a rotary tablet press (HT-AP15, manufactured by Utsuka Co., Ltd.) to obtain plain tablets (formulation example 1) (see Table 1).

A coating solution having a solid content of 10% by weight was prepared by dispersing the film-forming agent mixture in water (the composition of the film-forming agent mixture is shown in table 2 below). The plain tablets were coated by spraying a coating solution using a tablet coating machine (PRC-7, manufactured by Powrex corporation) so that the coating became 5 parts by weight in a dry state per 100 parts by weight of the plain tablets. The objective tablet was obtained by scattering carnauba wax in an amount of 0.03 wt% with respect to the base tablet and glazing.

The compositions of the obtained plain tablets and tablets are shown in tables 1 and 2 below.

[ Table 1]

Table 1: formulation example 1 (plain tablet) formulation

[ Table 2]

Table 2: formulation example 1 (plain tablet) film coating formulation

Composition (I)	1 in tablet (mg)	Content ratio (% by weight)
			Hydroxypropyl methylcellulose	3.90	60.0
Titanium oxide	1.46	22.4
			Lactose hydrate	0.65	10.0
Glycerol triacetate	0.39	6.0
			Yellow iron oxide	0.10	1.5
Iron oxide	0.01	0.1
			Total up to	6.50	100.0

Formulation example 2

500.0g of a solid dispersion (produced by spray drying, hereinafter referred to as "solid dispersion") containing 40% by weight of Compound A (Methylpadrolone "), 2068.0g of silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma), 1796.0g of lactose hydrate (Japanese pharmacopoeia), 236.1g of hypromellose (TC-5E, manufactured by shin-Etsu chemical Co., Ltd.), 520.0g of low-substitution hydroxypropylcellulose (L-HPC, manufactured by shin-Etsu chemical Co., Ltd.), and 40.0g of light silicic anhydride (Adsolider101, manufactured by Freund Corporation) were mixed by using a mixer (TBM-25, manufactured by Deshou John Co., Ltd.). To the mixture was added 20.0g of magnesium stearate, and further mixed. The mixture was dry granulated and granulated using a roll press (CCS-220, manufactured by Powrex Co., Ltd.). Magnesium stearate in an amount of 0.38 wt% of the obtained whole granules was added and mixed to obtain a mixed product for tableting. Tablets (weight: 130mg, shape of tablet: round (diameter: 7mm)) were prepared using a rotary tablet press (HT-AP15, manufactured by Usche corporation, and thereby, a tablet containing 5mg of Compound A (formulation example 2) was obtained (see Table 3).

A coating solution having a solid content of 10% by weight was prepared by dispersing the film-forming agent mixture in water (the composition of the film-forming agent mixture is shown in table 4 below). The plain tablets were coated by spraying a coating solution using a tablet coating machine (PRC-7, manufactured by Powrex corporation) so that the coating became 5 parts by weight in a dry state per 100 parts by weight of the plain tablets. The objective tablet was obtained by scattering carnauba wax in an amount of 0.03 wt% with respect to the base tablet and glazing.

Formulation example 3

A mixed product was prepared in the same manner as in formulation example 2, which was a 5mg tablet, and tabletted (weight: 260mg, shape of tablet: circular (diameter: 9mm)) using a rotary tablet press (HT-AP15, manufactured by Utility model Co., Ltd., tanaka), to obtain a tablet containing 10mg of Compound A (formulation example 3) (see Table 3).

A coating solution having a solid content of 15 wt% was prepared by dispersing the film-forming agent mixture in water (the composition of the film-forming agent mixture is shown in table 4 below). Coating was performed by spraying a coating solution onto 200g of the plain tablets using a tablet coating machine (DRC-200, manufactured by Powrex) so that the coating became 4 parts by weight in a dry state per 100 parts by weight of the plain tablets. The objective tablet was obtained by scattering carnauba wax in an amount of 0.03 wt% with respect to the base tablet and glazing.

Formulation example 4

A mixed product was prepared in the same manner as in formulation example 2, which was a 5mg tablet, and tabletted using a rotary tablet press (HT-AP15, manufactured by Hairkuzu iron-works Co., Ltd.) to obtain a tablet (weight: 390mg, tablet shape: oval (major axis: 13.5mm, minor axis: 7mm)) containing 15mg of Compound A (formulation example 4) (see Table 3).

A coating solution having a solid content of 15 wt% was prepared by dispersing the film-forming agent mixture in water (the composition of the film-forming agent mixture is shown in table 4 below). Coating was performed by spraying the coating solution using a tablet coating machine (PRC-7, manufactured by Powrex corporation) so that the coating became 3.5 parts by weight in a dry state per 100 parts by weight of the base tablet. The objective tablet was obtained by scattering carnauba wax in an amount of 0.03 wt% with respect to the base tablet and glazing.

The compositions of the obtained plain tablets and tablets are shown in tables 3 and 4 below.

[ Table 3]

Table 3: formulation examples 2 to 4 (plain tablets)

[ Table 4]

Table 4: formulation for film coating and adding gloss agent to formulation examples 2-4 (plain tablets)

In table 4, the objective tablets can also be obtained by polishing with magnesium stearate as a gloss agent instead of carnauba wax.

Mixing of common blend of plain tablets 1 to 3

336.5g of a solid dispersion containing 40% by weight of Compound A, 807.7g of silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma), and 13.5g of light silicic anhydride were mixed in a plastic bag 200 times to obtain a mixture (I) containing Compound A. Separately, 631.9g of silicic acid-treated crystalline cellulose and 11.9g of light silicic anhydride were mixed in a plastic bag 200 times to obtain a mixture (II).

Example 1: preparation method of plain tablet 1

215.0g of the above-mentioned mixture (I), 210.5g of lactose hydrate, 19.5g of hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Nippon Caoda corporation) and 32.5g of croscarmellose sodium (Ac-Di-Sol, manufactured by FMC Biopolymer) were mixed in a plastic bag 200 times, and further 2.5g of magnesium stearate (Parteck LUB, Merck) was added and further mixed 50 times. The resulting mixture was dry-granulated using a dry granulator (TF-Labo, manufactured by Freund Corporation). The obtained dry granulated product was granulated using a granulator (Comil, manufactured by Powrex corporation). The resulting whole pellet 443.1g, the above-mentioned mixed product (II)124.6g and croscarmellose sodium (Ac-Di-Sol, manufactured by FMC Biopolymer) 30.0g were mixed in a plastic bag 200 times, and then magnesium stearate 2.3g was added and mixed 50 times to obtain a mixture for tableting. Tableting (weight 130mg, tablet shape: round (diameter 7mm)) was performed using a rotary tableting machine (VIRGO, manufactured by chrysanthemums), whereby a plain tablet 1 was obtained.

Example 2: preparation method of plain tablet 2

148.9g of the above-mentioned blend (I), 145.7g of lactose hydrate, 13.5g of hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Nippon Caoda corporation) and 22.5g of low-substituted hydroxypropyl cellulose (L-HPC, manufactured by shin-Etsu chemical Co., Ltd.) were mixed in a plastic bag 200 times, and 1.7g of magnesium stearate (Parteck LUB, Merck) was added and further mixed 50 times. The resulting mixture was dry-granulated using a dry granulator (TF-Labo, manufactured by Freund Corporation). The obtained dry granulated product was granulated using a granulator (Comil, Powrex). 295.4g of the obtained whole granules, 83.1g of the above-mentioned blend (II), and 20.0g of low-substituted hydroxypropylcellulose (L-HPC, manufactured by shin Etsu chemical Co., Ltd.) were mixed in a plastic bag 200 times, and 1.5g of magnesium stearate was added thereto and mixed 50 times to obtain a mixture for tableting. Tableting (weight 130mg, tablet shape: round (diameter 7mm)) was performed using a rotary tableting machine (VIRGO, manufactured by chrysanthemums), whereby a plain tablet 2 was obtained.

Example 3: preparation method of plain tablet 3

148.9g of the above-mentioned mixture (I), 145.7g of lactose hydrate, 13.5g of hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Nippon Caoda corporation) and 22.5g of sodium starch glycolate (Primojel, DFE Pharma) were mixed in a plastic bag 200 times, and 1.7g of magnesium stearate (Parteck LUB, Merck) was added thereto and further mixed 50 times. The resulting mixture was dry-granulated using a dry granulator (TF-Labo, manufactured by Freund Corporation). The obtained dry granulated product was granulated using a granulator (Comil, manufactured by Powrex corporation). 295.4g of the obtained whole grain product, 83.1g of the above-mentioned mixture (II), and 20.0g of sodium starch glycolate (Primojel, DFE Pharma) were mixed in a plastic bag 200 times, and 1.5g of magnesium stearate was added thereto and mixed 50 times to obtain a mixture for tableting. Tableting (weight 130mg, tablet shape: round (diameter 7mm)) was performed using a rotary tableting machine (VIRGO, manufactured by chrysanthemums), whereby a plain tablet 3 was obtained.

Test example 1: comparative test for stability of base tablets 1 to 3 obtained in examples 1, 2 and 3

Measurement of substance analogous to bardoxolone methyl was determined by performing an experiment using liquid chromatography under the following conditions. As a column for liquid chromatography, ACQUITY UPLC HSS C18, particle size 1.8 μm, 2.1 mm. times.50 mm (manufactured by Waters) or equivalent thereof was used, and the column temperature was maintained at 40 ℃. 20mmol/L sodium dihydrogen phosphate/citric acid buffer (pH4.5) was used as mobile phase A, and acetonitrile was used as mobile phase B. The sample solution was diluted with 65 wt% acetonitrile so that the concentration of bardoxolone methyl was 100. mu.g/mL. The total amount (%) of each analog substance was determined by performing similar substance measurement using an ultraviolet absorptiometer (measurement wavelength: 242nm) at a flow rate of 0.6mL/min, relative to the amount of bardoxolone expressed.

The stability test was carried out under the following conditions.

Storage conditions are as follows: 30 ℃ and 75% RH for 1 month

And (4) preservation form: putting 1-3 plain tablets into a brown bottle with a cover opened

[ Table 5]

Table 5: comparison results of stability of plain tablets 1 to 3

From the results of table 5 above, it is clear that the total amount of the similar substances is small and the preparation is excellent in stability when any disintegrant is added (in addition, although data is not shown, the amount of increase in the total amount of the similar substances from the beginning is small when any disintegrant is added). As can be seen from a comparison of the above three types of plain tablets, plain tablets containing low-substitution hydroxypropylcellulose as a disintegrant exhibited the most excellent overall stability with a small total amount (and an increased amount) of similar substances.

Example 4: preparation method of plain tablet 4

Compound a44.2g, silicic acid-treated crystalline cellulose 110.4g, light silicic anhydride 1.8g, lactose hydrate 176.9g, and hypromellose (TC-5E, manufactured by shin-Etsu chemical Co., Ltd.) 4.6g were mixed in a plastic bag 200 times, and magnesium stearate (Parteck LUB, Merck)1.8g was added and further mixed 50 times. The resulting mixture was dry-granulated using a dry granulator (TF-Labo, manufactured by Freund Corporation). The obtained dry granulated product was granulated using a granulator (Comil, manufactured by Powrex corporation). 295.4g of the whole granules, 81.5g of silicic acid-treated crystalline cellulose, 1.5g of light silicic anhydride, and 20g of croscarmellose sodium (Ac-Di-Sol, manufactured by FMC Biopolymer) were mixed in a plastic bag 200 times, 1.5g of magnesium stearate was further added, and the mixture was mixed 50 times to obtain a mixture for tableting. Tableting (weight 130mg, tablet shape: round (diameter 7mm)) was performed using a rotary tableting machine (VIRGO, manufactured by chrysanthemums), whereby a plain tablet 4 was obtained.

Example 5: preparation method of plain tablet 5

Compound A44.2g, silicic acid-treated crystalline cellulose 90.9g, light silicic anhydride 1.8g, lactose hydrate 159.6g, hypromellose (TC-5E, manufactured by shin-Etsu chemical Co., Ltd.) 41.4g were mixed in a plastic bag 200 times, and magnesium stearate (Parteck LUB, Merck)1.8g was added and further mixed 50 times. The resulting mixture was dry-granulated using a dry granulator (TF-Labo, manufactured by Freund Corporation). The obtained dry granulated product was granulated using a granulator (Comil, manufactured by Powrex corporation). 295.4g of the whole granules, 81.5g of silicic acid-treated crystalline cellulose, 1.5g of light silicic anhydride, and 20.0g of croscarmellose sodium (Ac-Di-Sol, manufactured by FMC Biopolymer) were mixed in a plastic bag for 200 times, and 1.5g of magnesium stearate was added thereto and mixed for 50 times to obtain a mixture for tableting. Tableting (weight 130mg, tablet shape: round (diameter 7mm)) was performed using a rotary tableting machine (VIRGO, manufactured by chrysanthemums), whereby a plain tablet 5 was obtained.

Example 6: preparation method of plain tablet 6

Compound a44.2g, silicic acid-treated crystalline cellulose 98.0g, light silicic anhydride 1.8g, lactose hydrate 166.3g, and hypromellose (TC-5E, manufactured by shin-Etsu chemical Co., Ltd.) 4.6g were mixed in a plastic bag 200 times, and magnesium stearate (Parteck LUB, Merck)1.8g was added and further mixed 50 times. The resulting mixture was dry-granulated using a dry granulator (TF-Labo, manufactured by Freund Corporation). The obtained dry granulated product was granulated using a granulator (Comil, manufactured by Powrex corporation). 275.4g of the whole granules, 81.5g of silicic acid-treated crystalline cellulose, 1.5g of light silicic anhydride, and 40.0g of low-substituted hydroxypropylcellulose (L-HPC, manufactured by shin-Etsu chemical Co., Ltd.) were mixed in a plastic bag 200 times, and 1.5g of magnesium stearate was added thereto and mixed 50 times to obtain a mixture for tableting. Tableting (weight 130mg, tablet shape: round (diameter 7mm)) was performed using a rotary tableting machine (VIRGO, manufactured by chrysanthemums), whereby a plain tablet 6 was obtained.

Example 7: preparation method of plain tablet 7

Compound a44.2g, silicic acid-treated crystalline cellulose 78.2g, light silicic anhydride 1.8g, lactose hydrate 149.3g, and hypromellose (TC-5E, manufactured by shin-Etsu chemical Co., Ltd.) 41.4g were mixed in a plastic bag 200 times, and magnesium stearate (Parteck LUB, Merck)1.8g was added and further mixed 50 times. The resulting mixture was dry-granulated using a dry granulator (TF-Labo, manufactured by Freund Corporation). The obtained dry granulated product was granulated using a granulator (Comil, Powrex). 275.4g of the whole granules, 81.5g of silicic acid-treated crystalline cellulose, 1.5g of light silicic anhydride, and 40.0g of low-substituted hydroxypropylcellulose (L-HPC, manufactured by shin-Etsu chemical Co., Ltd.) were mixed in a plastic bag 200 times, and 1.5g of magnesium stearate was added thereto and mixed 50 times to obtain a mixture for tableting. Tableting (weight 130mg, tablet shape: round (diameter 7mm)) was performed using a rotary tableting machine (VIRGO, manufactured by chrysanthemums), whereby a plain tablet 7 was obtained.

The compositions of the disintegrant and binder in the above plain tablets 4 to 7 are as follows.

[ Table 6]

Table 6: composition of disintegrant and binder in 4-7 tablets per 1 tablet (130mg)

Test example 2: comparative test for elution Properties of plain tablets 4 to 7 obtained in examples 4, 5, 6 and 7

The obtained plain tablets 4 to 7 were put into brown glass bottles and stored in an uncapped state at 30 ℃ and 75% relative humidity for 1 month, 2 months, and 3 months before (at the beginning of) storage.

The dissolution test was carried out according to the Japanese pharmacopoeia dissolution test 2 (paddle method, 50 rpm). The test solution used was 900mL of the japanese pharmacopoeia dissolution test solution 2 containing 0.15 wt% of sodium lauryl sulfate, and the dissolution rates of compound a at 5, 10, 15, 30, 45, 60, 90, 120, and 135 minutes from the start of the test were evaluated by liquid chromatography. As the column, ACQUITY UPLC HSS C18, particle size 1.8 μm, 2.1 mm. times.50 mm (manufactured by Waters), or equivalent thereof was used, and maintained at 40 ℃. As mobile phase A, 20mmol/L sodium dihydrogen phosphate/citric acid buffer (pH4.5) was used, and as mobile phase B, acetonitrile was used. The measurement was carried out using an ultraviolet absorptiometer (measurement wavelength: 242nm) at a flow rate of 0.6 mL/min.

The results of the dissolution rates (%) of the plain film 4 to 7 before (at the beginning of) storage, after 1 month (1 month), after 2 months (2 months), and after 3 months (3 months) are shown in fig. 1 to 4. In order to obtain an excellent preparation with a small variation in dissolution rate depending on the storage period of the base tablet, it was found that in the presence of a binder, the compound a had a small variation in dissolution rate even when either croscarmellose sodium or low-substituted hydroxypropylcellulose (L-HPC) was used as a disintegrant, and that a good dissolution rate was obtained for any base tablet (base tablets 4 to 7).

In addition, when these two disintegrants are compared, the low-substituted hydroxypropylcellulose (L-HPC) has a smaller variation than croscarmellose sodium, and it is known that low-substituted hydroxypropylcellulose (L-HPC) is a more preferable disintegrant for compound a.

Example 8: process for the preparation of tablet 1

144.2g of a solid dispersion containing 40% by weight of Compound A, 346.2g of silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma), 564.2g of lactose hydrate (Japanese pharmacopoeia), and 5.8g of light silicic anhydride were mixed to obtain a mixture containing Compound A. 494.8g of this mixture was mixed with 19.4g of hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Nippon Caoda corporation) in a plastic bag for 200 times, and 2.7g of magnesium stearate was further mixed in the plastic bag for 50 times. The mixture was dry-granulated using a roll press (TF-Labo, manufactured by Freund Corporation). The obtained dry granulated product was granulated using a granulator (Comil, manufactured by Powrex corporation). 480g of the obtained whole grain product, 132.5g of silicic acid-treated crystalline cellulose, 2.5g of light silicic anhydride, and croscarmellose sodium (Ac-Di-Sol, manufactured by FMC Biopolymer) were mixed in a plastic bag. Further, 2.5g of magnesium stearate was added thereto, and the mixture was rotary-mixed 50 times in a plastic bag to obtain a tablet mixture. Tableting was performed using a rotary tableting machine (VIRGO, manufactured by chrysanthemums) (weight: 130mg, shape of tablet: round (diameter 7mm)), thereby obtaining a plain tablet.

Coating solutions were prepared by dispersing each of the coating agent mixtures in water (the composition of the coating agent mixture and the solid content concentration of the coating solution are shown in table 7 below). To 200g of the plain tablets, each coating solution was sprayed using a tablet coating machine (DRC-200, manufactured by Powrex) so that the coating became 5 parts by weight in a dry state per 100 parts by weight of the plain tablets, and coating was performed, thereby obtaining the objective tablets 1.

Example 9: process for the preparation of tablet 2

Coating solutions were prepared by dispersing each of the coating agent mixtures in water (the composition of the coating agent mixture and the solid content concentration of the coating solution are shown in table 7 below). The coating solution was sprayed on 200g of the base tablet using a tablet coating machine (DRC-200, manufactured by Powrex) so that the coating became 5 parts by weight in a dry state per 100 parts by weight of the base tablet, and the target tablet 2 was obtained.

[ Table 7]

Table 7: film coating formulation

Test example 3: comparison of the stability of film-coated tablets obtained in examples 8 and 9

Measurement of substance analogous to bardoxolone methyl test was carried out by liquid chromatography under the following conditions. As the column, ACQUITY UPLC HSS C18, particle size 1.8 μm, 2.1 mm. times.50 mm (manufactured by Waters), or equivalent thereof was used, and maintained at 40 ℃. As mobile phase A, 20mmol/L sodium dihydrogen phosphate/citric acid buffer (pH4.5) was used, and as mobile phase B, acetonitrile was used. As the sample solution, a solution diluted with 65 wt% acetonitrile so that the concentration of the compound became 100. mu.g/mL was used. The total amount (%) of each analog substance was determined by performing similar substance measurement using an ultraviolet absorptiometer (measurement wavelength: 242nm) at a flow rate of 0.6mL/min, relative to the amount of bardoxolone expressed.

The stability test was carried out under the following conditions.

Storage conditions are as follows: 30 ℃ and 75% RH for 1 month

And (4) preservation form: tablets 1 and 2 were placed in a brown bottle with the lid open

[ Table 8]

Table 8: results of comparison of stability of film-coated tablets (tablets 1 and 2) obtained in examples 8 and 9

From the results of table 8, it is understood that when any film coating formulation is used, a good preparation having a high stability and a small total amount of the similar substances is obtained as long as the tablet contains compound a, a disintegrant, and a binder and has a coating film.

It is found that a good preparation with a small total amount of the analogous substance and high stability can be obtained by adding triacetin to the film coating formulation.

Example 10: formulation example 2 and preparation method of plain tablet 8

19.2g of a solid dispersion containing 40% by weight of Compound A, 79.5g of silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma), 69.1g of lactose hydrate, 9.1g of hypromellose (TC-5E, shin-Etsu chemical industry), 20g of low-substituted hydroxypropylcellulose (L-HPC, shin-Etsu chemical industry), and 1.5g of light silicic anhydride (Adsolider101, Freund Corporation) were mixed in a plastic bag, and 0.8g of magnesium stearate (Perteck LUB MST, Merck) was further added thereto and mixed to obtain a mixture of the same formulation example 2 as described above.

19.2g of a solid dispersion containing 40% by weight of Compound A, 78.5g of silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma), 68.2g of lactose hydrate, 9.1g of hypromellose (TC-5E, shin-Etsu chemical industry), 20.0g of low-substituted hydroxypropylcellulose (L-HPC, shin-Etsu chemical industry), 1.5g of light silicic anhydride (Adsollder 101, Freund Corporation), and 2.0g of an organic acid (stabilizer) were mixed in a plastic bag, and further 0.8g of magnesium stearate (Perteck LUB MST, Merck) was added thereto, followed by mixing to obtain a mixture containing 1% by weight of an organic acid.

The resulting mixture was dry-granulated using a dry granulator (TF-Labo, Freund Corporation). The obtained dry granulated product was granulated by using a granulator (Comil, Powrex). To the obtained whole granules, magnesium stearate (perceck LUB MST, Merck) was added in an amount of 0.38 wt%, and the mixture was mixed in a plastic bag 50 times to obtain a mixture for tableting. Tableting (weight 130mg, tablet shape: round (diameter 7mm)) was performed using a rotary tableting machine (VIRGO, manufactured by chrysanthemums), whereby plain tablets 8 (containing an organic acid) were obtained. The composition of the base sheet 8 is shown in table 9 below. For reference, the composition of formulation example 2 is also shown.

[ Table 9]

Table 9: formulation example 2 (plain tablet) and composition of plain tablet 8

Test example 4: stability by whether or not an organic acid was added to formulation example 2 (plain tablets) and plain tablet 8 obtained in example 10 Comparative test of Properties

Measurement of substance analogous to bardoxolone methyl was determined by performing an experiment using liquid chromatography under the following conditions. Specifically, ACQUITY UPLC HSS C18, particle size 1.8 μm, 2.1 mm. times.50 mm (manufactured by Waters), or equivalent thereof was used as a column and maintained at 40 ℃. As mobile phase A, 10mmol/L phosphate buffer (pH2.5) was used, and as mobile phase B, acetonitrile was used. As the sample solution, a solution prepared by diluting a mobile phase A and an acetonitrile mixed solution (4: 6) so that the concentration of the compound becomes 400. mu.g/mL was used. The total amount (%) of each analog substance was determined by performing similar substance measurement using an ultraviolet absorptiometer (measurement wavelength: 242nm) at a flow rate of 0.3mL/min, relative to the amount of bardoxolone expressed.

The stability test was carried out under the following conditions.

Storage conditions are as follows: 40 deg.C, 75% RH, 1 or 2 months

And (4) preservation form: in a brown bottle with a cap opened, formulation example 2 (plain tablets) and plain tablets 8(5 kinds)

[ Table 10]

Table 10: the total amount of the similar substances (%)% in formulation example 2 (plain tablet) and plain tablet 8 obtained in example 10

From the results of Table 10 above, it is understood that the amount of the similar substances is less increased when any of the organic acids is added (plain film 8) than when no organic acid is added (formulation example 2). In addition, of these organic acids, the total amount of the similar substances and the amount of the similar substances (1 month and 2 months) were small, particularly in the formulations containing fumaric acid and malic acid.

Production of aluminum bag packages 1 to 3

A base tablet was prepared by the same procedure as in formulation example 2. Specifically, as described below.

500.0g of a solid dispersion (produced by spray drying, hereinafter referred to as "solid dispersion") containing 40% by weight of Compound A (Methylpadrolone "), 2068.0g of silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma), 1796.0g of lactose hydrate (Japanese pharmacopoeia), 236.0g of hypromellose (TC-5E, manufactured by shin-Etsu chemical Co., Ltd.), 520.0g of low-substitution hydroxypropylcellulose (L-HPC, manufactured by shin-Etsu chemical Co., Ltd.), and 40.0g of light silicic anhydride (Adsolider101, manufactured by Freund Corporation) were mixed by using a mixer (TBM-25, manufactured by Deshou John Co., Ltd.). To the mixture was added 20.0g of magnesium stearate, and further mixed. The mixture was dry granulated and granulated using a roll press (CCS-220, manufactured by Powrex Co., Ltd.). Magnesium stearate in an amount of 0.38 wt% of the obtained whole granules was added and mixed to obtain a mixed product for tableting. Tablets (weight: 130mg, shape of tablet: round (diameter: 7mm)) were prepared using a rotary tablet press (HT-AP15, manufactured by Usche corporation, and) to obtain a tablet X containing 5mg of Compound A. The obtained plain tablet X was coated with a film coat and carnauba wax in the same manner as in formulation example 2, and polished to obtain the desired tablet X.

The compositions of the obtained plain tablets X and tablets X are shown in tables 11 and 12 below.

[ Table 11]

Table 11: formula of plain tablet X

[ Table 12]

Table 12: formula for film coating of plain tablets X and adding gloss agent

For tablets X prepared according to the formulations of tables 11 and 12, PTP packages 1 to 3 were obtained using an Aclar (trademark) film (Sumilite (trademark) FCL-1122, manufactured by Sumitomo Bakelite co.) (hereinafter, also referred to as "Aclar") or a hard vinyl chloride film (Sumilite (trademark) VSS, manufactured by Sumitomo Bakelite co.) (hereinafter, also referred to as "hard vinyl chloride") or a polypropylene film (TAS2230V, manufactured by kaiki armoi corporation) (hereinafter, also referred to as "polypropylene") and an aluminum foil (manufactured by Tokai Toyo aluminum Hanbai corporation or UACJ foil co., manufactured by PTP packaging machine (PFD-100, manufactured by Maruho Hatsujyo Kogyo co). The obtained blister pack 3 sheets and a desiccant (MS-serum-W3G, manufactured by east sea chemical industry) were put in an aluminum bag and sealed by a heat sealer (V-301-10W, manufactured by Fuji Impulse co., ltd.) to obtain the intended aluminum bag packs 1 to 3.

Production of aluminum bag packaged products 4-6

The same procedures as for aluminum pouch packages 1 to 3 were carried out to obtain green sheets Y, tablets Y, blister packages 4 to 6, and aluminum pouch packages 4 to 6, except that 12.0g of an organic acid (0.2 wt% of organic acid (fumaric acid) was added together with compound a (bardoxolone methyl) to reduce the silicic acid-treated crystalline cellulose to 2060.0g and the lactose hydrate to 1792.0 g.

Test example 5: comparative test of stability of aluminum bag packages 1 to 6

With respect to the aluminum pouch packages 1 to 6 (hereinafter, also referred to as "packages 1 to 6"), the total amount (%) of similar substances was measured under the same storage conditions (40 ℃, 75% RH, 1 month open) as in test example 4 (at "start time" and "40 ℃, 75% RH, 1 month open"). The results are shown in table 13 below. Measurement of a substance analogous to bardoxolone methyl was carried out by a liquid chromatography test under the same conditions as in test example 4.

[ Table 13]

Table 13: total amount of similar substances (%)% after storage of aluminum bag-packed products 1 to 6

From the results in tables 10 and 13 and table 14 below, it is understood that the increase in the total amount (%) of the similar substances is suppressed and the stability is improved by producing the aluminum pouch-packed product. From the results in table 13, it is found that the following tendency is observed when 0.2 wt% of an organic acid (fumaric acid) is added to the aluminum bag package based on the total weight of the base sheet: increase in the total amount (%) of the similar substances is suppressed and stability is improved. Further, it is found that when a rigid vinyl chloride film or a polypropylene film is used in an aluminum bag package, the increase in the total amount (%) of the similar substances is further suppressed and the stability is further improved, as compared with an Aclar (trademark) film (polychlorotrifluoroethylene).

Test example 6: aluminum bag packageStudy on the stability of the product

With respect to the tablet X and blister pack 1 (using Aclar) (not put in an aluminum bag) obtained in the production process of the aluminum bag packages 1 to 3, the total amount (%) of similar substances was measured under the same storage conditions (40 ℃, 75% RH, 1 month open) and storage state (tablet X was put in a brown glass bottle with an open lid) as in the above-described test examples 4 and 5 ("start time" and "40 ℃, 75% RH, 1 month open"). The results are shown in table 14 below. Measurement of a substance analogous to bardoxolone methyl was carried out by a liquid chromatography test under the same conditions as in test example 4.

[ Table 14]

Table 14: total amount of similar substances (%)% after storage of tablet X and blister pack 1

From the results of tables 13 and 14 above, it is understood that the total amount of similar substances and the amount of increase thereof are smaller in the blister pack 1 and the aluminum pouch pack 1 of tablet X as compared with tablet X (film coating formulation). It is also known that the total amount of several similar substances in the aluminium pouch package 1 of tablet X and the increase thereof are less compared to the blister package 1. Accordingly, it is found that the stability can be improved by using the film coating formulation of the present invention as a blister pack, and that the stability can be further improved by using the film coating formulation of the present invention as an aluminum pouch pack.

Test example 7: comparative testing of stability in film coating formulations

The following tests were used: tablet X used in the comparative test of test example 5 above; tablet Y-1 prepared in such a manner that 1% by weight, instead of 0.2% by weight, of fumaric acid is contained in the plain tablet of tablet Y; and a tablet Z prepared so that 1 wt% of malic acid is contained in the base tablet instead of fumaric acid contained in the tablet Y. Tablet X, tablet Y-1, and tablet Z are film coating formulations. The total amount (%) of the analogous substances was measured for the thus-prepared tablet X, tablet Y-1 and tablet Z under the same storage conditions and liquid chromatography conditions as those of test example 5 (data not shown). As a result, it was found that, in the case of the tablet Y-1 (containing fumaric acid) and the tablet Z (containing malic acid) prepared by adding an organic acid (fumaric acid or malic acid), the increase in the total amount (%) of the analogous substance was further suppressed and the stability was further improved as compared with the tablet X prepared without adding an organic acid. It is also found that the tablet Y-1 prepared by adding fumaric acid and the tablet Z prepared by adding malic acid are almost indistinguishable from each other in terms of the amount of increase in the total (%) of the similar substances from the beginning.

Claims

1. A pharmaceutical composition comprising bardoxolone methyl or a pharmaceutically acceptable salt thereof, a disintegrant and a binder, said pharmaceutical composition having a coating film.

2. The pharmaceutical composition according to claim 1, wherein the disintegrant is 1 or more selected from the group consisting of crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, partially gelatinized starch, and starch.

3. The pharmaceutical composition according to claim 2, wherein the disintegrant is 1 or more selected from the group consisting of crospovidone, croscarmellose sodium, and low-substituted hydroxypropyl cellulose.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the disintegrant is contained in an amount of 0.1 to 20 parts by weight per 100 parts by weight of the pharmaceutical composition.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the binder is 1 or more selected from the group consisting of hydroxypropyl cellulose, methyl cellulose, hypromellose, carboxymethyl cellulose, carboxymethylethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxypropyl starch, carboxyvinyl polymer, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, methacrylic acid copolymer, polyethylene glycol, starch, gelatin, dextrin, pullulan, agar, and gum arabic.

6. The pharmaceutical composition according to claim 5, wherein the binder is 1 or more selected from the group consisting of hydroxypropyl cellulose, hypromellose, polyvinyl alcohol, and polyvinylpyrrolidone.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the binder is contained in an amount of 0.1 to 30 parts by weight based on 100 parts by weight of the pharmaceutical composition.

8. The pharmaceutical composition of any one of claims 1-7, further comprising a stabilizer.

9. The pharmaceutical composition of claim 8, wherein the stabilizer is an organic acid.

10. The pharmaceutical composition according to claim 9, wherein the organic acid is fumaric acid and/or malic acid.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the coating film comprises 1 or more coating agents selected from the group consisting of water-soluble polymers, lactose, white sugar, mannitol, titanium oxide, talc, calcium carbonate, and triacetin.

12. The pharmaceutical composition of claim 11, wherein the water-soluble polymer is 1 or more selected from the group consisting of polyethylene glycol, polyvinyl alcohol polyethylene glycol graft copolymer, polyvinylpyrrolidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, and polyvinyl alcohol methyl acrylate copolymer.

13. The pharmaceutical composition according to claim 11 or 12, wherein the coating envelope further comprises a coloring agent.

14. The pharmaceutical composition of claim 13, wherein the colorant comprises 1 or more selected from the group consisting of yellow iron trioxide, iron oxide, and titanium oxide.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the coating agent is contained in an amount of 0.1 to 100 parts by weight based on 100 parts by weight of the coating film.

16. The pharmaceutical composition of any one of claims 1-15, further comprising a glossing agent.

17. The pharmaceutical composition according to claim 16, wherein the gloss agent is carnauba wax and/or magnesium stearate.

18. The pharmaceutical composition of any one of claims 1 to 17,

19. A pharmaceutical composition as claimed in any one of claims 1 to 18 wherein bardoxolone methyl is amorphous.

20. The pharmaceutical composition of any one of claims 1-19, which is a solid formulation.

21. The pharmaceutical composition of claim 20, wherein the solid dosage form is a tablet.

22. A blister package comprising the pharmaceutical composition of any one of claims 1 to 21, and a film and aluminum foil laminated with a polymer.

23. The blister package according to claim 22, wherein the polymer laminated film is a film laminated with 1 or more polymers selected from the group consisting of polypropylene, polyvinyl chloride, polyvinylidene chloride, and polychlorotrifluoroethylene.

24. A pharmaceutical pack comprising a package in which a blister pack according to claim 22 or 23 is enclosed.

25. The pharmaceutical package of claim 24, wherein the package is an aluminum bag.

26. The pharmaceutical package according to claim 24 or 25, wherein a deoxidant and/or a desiccant are further enclosed in the package.